The present invention relates to benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.
Of the DNA viruses, those of the herpes group are the sources of the most common viral illnesses in man. The group includes herpes simplex virus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6) and human herpes virus type 7 (HHV-7). HSV-1 and HSV-2 are some of the most common infectious agents of man. Most of these viruses are able to persist in the host""s neural cells; once infected, individuals are at risk of recurrent clinical manifestations of infection which can be both physically and psychologically distressing.
HSV infection is often characterised by extensive and debilitating lesions of the skin, mouth and/or genitals. Primary infections may be subclinical although tend to be more severe than infections in individuals previously exposed to the virus. Ocular infection by HSV can lead to keratitis or cataracts thereby endangering the host""s sight. Infection in the new-born, in immunocompromised patients or penetration of the infection into the central nervous system can prove fatal.
VZV is a herpes virus which causes chickenpox and shingles. Chickenpox is the primary disease produced in a host without immunity, and in young children is usually a mild illness characterised by a vesicular rash and fever. Shingles or zoster is the recurrent form of the disease which occurs in adults who were previously infected with VZV. The clinical manifestations of shingles are characterised by neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation may lead to paralysis or convulsions. Coma can occur if the meninges become affected. VZV is of serious concern in patients receiving immunosuppressive drugs for transplant purposes or for treatment of malignant neoplasia and is a serious complication of AIDS patients due to their impaired immune system.
In common with other herpes viruses, infection with CMV leads to a lifelong association of virus and host. Congenital infection following infection of the mother during pregnancy may give rise to clinical effects such as death or gross disease (microcephaly, hepatosplenomegaly, jaundice, mental retardation), retinitis leading to blindness or, in less severe forms, failure to thrive, and susceptibility to chest and ear infections. CMV infection in patients who are immunocompromised for example as a result of malignancy, treatment with immunosuppressive drugs following transplantation or infection with Human Immunodeficiency Virus, may give rise to retinitis, pneumonitis, gastrointestinal disorders and neurological diseases.
The main disease caused by EBV is acute or chronic infectious mononucleosis (glandular fever). Examples of other EBV or EBV associated diseases include lymphoproliferative disease which frequently occurs in persons with congenital or acquired cellular immune deficiency, X-linked lymphoproliferative disease which occurs namely in young boys, EBV-associated B-cell tumours, Hodgkin""s disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin-cell lymphoma, thymomas and oral hairy leukoplakia. EBV infections have also been found in association with a variety of epithelial-cell-derived tumours of the upper and lower respiratory tracts including the lung.
HHV-6 has been shown to be a causative agent of infantum subitum in children and of kidney rejection and interstitial pneumonia in kidney and bone marrow transplant patients, respectively, and may be associated with other diseases such as multiple sclerosis. There is also evidence of repression of stem cell counts in bone marrow transplant patients. HHV-7 is of undetermined disease aetiology.
Hepatitis B virus (HBV) is a viral pathogen of world-wide major importance. The virus is aetiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world""s liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above.
PCT Patent Specification Nos. WO 92/07867 and WO 94/08456 describe certain antiviral polysubstituted benzimidazole nucleoside analogues including -D-ribofuranosyl riboside analogues. PCT Patent Specification No. WO 93/18009 describes certain antiviral benzimidazole analogues in which the sugar residue is replaced by a carbocyclic group.
It has now been discovered that certain L-sugar substituted benzimidazole compounds as referred to below, are useful for the treatment or prophylaxis of certain viral infections. According to a first aspect of the present invention, novel compounds of the formula (I) are provided: 
wherein;
R1 represents hydrogen, a halo atom or azido;
xe2x80x94NR8R9 where R8 and R9, which may be the same or different, are each independently selected from hydrogen, hydroxyl, C1-12 alkyl, for example C1-6 alkyl (where the alkyl moiety may be optionally substituted by one or more substituents selected from halo, amino, azido, hydroxy, cyano, NO2, NHR10, SO2R10, SR10, OR10, COR10 and haloC1-6 alkyl where R10 is C1-6 alkyl, C3-6 alkenyl, C2-6 alkynyl, or aryl), C2-8 alkenyl, C1-6 alkoxy, C3-7 cycloalkyl, C2-8 alkynyl, C3-7 cycloalkenyl, C3-7 cycloalkylC1-6 alkyl, aryl, arylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkyl, heterocyclyl and heterocyclylC1-6 alkyl, or R8R9 together with the N atom to which they are attached form a 3,4,5 or 6 membered heterocyclic ring;
xe2x80x94NHNR11R12 where R11 and R12, which may be the same or different, each represent hydrogen or C1-6 alkyl;
xe2x80x94Nxe2x95x90NC1-6 alkyl or xe2x80x94NHOC1-6alkyl;
R2 represents hydrogen, halo atom, C1-6alkyl or C2-6alkenyl;
R3 and R4, which may be the same of different, each represent hydrogen, halogen or NO2;
R5 and R6, which may be the same or different, each represent hydrogen or hydroxy;
R7 represents hydrogen, CH3 or CH2R13 where R13 may be selected from hydroxy, a halo atom and OR14 (where R14 is hydrogen, C1-8alkyl, aryl or arylC1-6alkyl);
with the proviso that when R2 represents hydrogen, R3 and R4 each represent chloro, R5 and R6 represent an erythro hydroxy group and R7 is xe2x80x94CH2OH then R1 represents azido, xe2x80x94NR8R9 where R8 and R9, which may be the same or different, are each independently selected from hydroxyl, C1-6 alkyl (where the alkyl moiety is substituted by one or more substituents selected from amino, azido, NO2, NHR10, SO2R10, SR10, OR10, haloC1-6 alkyl where R10 is as hereinbefore defined), C7-12 alkyl (where the alkyl moiety is optionally substituted by one or more substituents selected from halo, amino, azido, hydroxy, cyano, NO2, NHR10, SO2R10 SR10, OR10, COR10 and haloC1-6 alkyl where R10 is as hereinbefore defined), C1-6 alkoxy, C3-7 cycloalkenyl, heteroaryl, heteroaryl C1-6 alkyl and heterocyclyl;
xe2x80x94NHNR11R12 where R11 and R12 are as hereinbefore defined;
xe2x80x94Nxe2x95x90NC1-6 alkyl or xe2x80x94NHOC1-6 alkyl;
or a pharmaceutically acceptable derivative thereof.
The present invention further provides compounds of formula (I) wherein the sugar moiety is selected from the following: 
Further examples of the compounds of formula (I) above include Examples 1 to 65 as described hereinafter.
As used herein the term alkyl as a group or part of a group means a straight or branched chain alkyl group. Such alkyl groups preferably have 1-6 carbon atoms, most preferably 1 to 4 and in particular include methyl, ethyl, i-propyl, t-butyl. References to alkenyl groups include groups which may be in the E- or Z- form or a mixture thereof and which when they contain at least three carbon atoms, may be branched. The term halo includes chloro, bromo, fluoro and iodo. The term haloC1-6 alkyl means an alkyl group in which one or more hydrogens is replaced by halo and preferably containing one, two or three halo groups. Examples of such groups include trifluoromethyl and fluoroisopropyl.
The term aryl as a group or part of a group means phenyl optionally substituted with one or more substituents selected from C1-6 alkoxy (for example, methoxy), nitro, a halo atom (for example chloro), amino, carboxylate and hydroxy. The term heterocyclyl as a group or part of a group means a saturated or partially saturated (i.e. non-aromatic) 3-,4-,5- or 6 membered ring containing one or more (for example one to four) heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of such groups include pyrrolidine. The term heteroaryl means a 4,5 or 6-membered aromatic ring containing one or more (for example one to four) heteroatoms independently selected from nitrogen, oxygen and sulphur, for example: pyrazole, pyrrole, imidazole, and pyridine.
The present invention includes within its scope each possible alpha and beta anomer of the compounds of formula (I) and their physiologically functional derivatives, substantially free of the other anomer, that is to say no more than about 5% w/w of the other anomer, preferably no more than about 2% w/w, in particular less than 1% w/w will be present, and mixtures of such alpha and beta anomers in any proportions. Compounds of formula (I) in the beta anomeric form are preferred.
Preferred compounds of formula (I) include those wherein:
(i) R1 is xe2x80x94NR8R9, where R8 and R9, which may be the same or different, are selected from C1-6alkyl or C3-7 cycloalkyl, preferably isopropyl or cyclopropyl;
(ii) R2 is hydrogen or a halo atom;
(iii) R3 and R4 are both a halo atom, preferably chloro;
(iv) the sugar moiety is 3xe2x80x2-deoxy-L-ribofuranosyl (formula (b) as hereinbefore defined);
(v) the sugar moiety is 5xe2x80x2-deoxy-L-ribofuranosyl (formula (c) as hereinbefore defined);
(vi) the sugar moiety is 2xe2x80x2-deoxy-L-ribofuranosyl (formula (f) as hereinbefore defined);
or a pharmaceutically acceptable derivative thereof.
Particularly preferred compounds of formula (I) include those wherein R1 is xe2x80x94NR8R9 wherein R8 is hydrogen and R9 is a C1-6 alkyl, preferably isopropyl or C3-7 cycloalkyl, preferably cyclopropyl;
R2 is hydrogen or a halo atom (for example bromo), R3 and R4 are both a halo atom, preferably chloro and the sugar moeity is selected from:
3xe2x80x2-deoxy-L-ribofuranosyl;
5xe2x80x2-deoxy-L-ribofuranosyl; and
2xe2x80x2-deoxy-L-ribofuranosyl;
or a pharmaceutically acceptable derivative thereof.
Preferred compounds according to the invention include:
4-Bromo-5,6-dichloro-2-isopropylamino-1-(beta-L-ribofuranosyl)1H-benzimidazole;
5,6-Dichloro-1-(3-deoxy-beta-L-ribofuranosyl)-2-isopropylamino-1H-benzimidazole;
5,6-Dichloro-1-(5-deoxy-beta-L-ribofuranosyl)-2-isopropylamino-1H-benzimidazole;
5,6-Dichloro-1-(beta-L-erythrofuranosyl)-2-isopropylamino-1H-benzimidazole;
5,6-Dichloro-2-isopropylamino-1-(beta-L-xylofuranosyl)-1H-benzimidazole;
1-(2-Deoxy-beta-L-ribofuranosyl)-5,6-dichloro-2-isopropylamino-1H-benzimidazole;
2-Isopropylamino-1-beta-L-ribofuranosyl)-4,5,6-trichloro-1H-benzimidazole;
4-Bromo-2-cyclopropylamino-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole;
2-Cyclopropylamino-1-(beta-L-ribofuranosyl)-4,5,6-trichloro-1H-benzimidazole;
4,6-Dichloro-2-isopropylamino-1-(beta-L-ribofuranosyl)-1H-benzimidazole;
1-(beta-L-Erythrofuranosyl)-2-isopropylamino-4,5,6-trichloro-1H-benzimidazole;
and pharmaceutically acceptable derivatives thereof.
The compounds of formula (I) above and their pharmaceutically acceptable derivatives are hereinafter referred to as the compounds according to the invention.
By xe2x80x9ca pharmaceutically acceptable derivativexe2x80x9d is meant any pharmaceutically or pharmacologically acceptable salt, ester or salt of such ester of a compound according to the invention, or any compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound according to the invention, or an antivirally active metabolite or residue thereof.
Preferred esters of the compounds according to the invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the 2xe2x80x2-, 3xe2x80x2- and/or 5xe2x80x2-hydroxy groups, in which the noncarbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C1-4 alkyl, or C1-4 alkoxy or amino); (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di(C6-24)acyl glycerol.
In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly form 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
Preferred carboxylic acid esters according to the present invention include the acetate, butyrate and valerate esters, L-valyl is a particularly preferred amino acid ester.
Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts include salts of organic carboxylic acids such as ascorbic, acetic, citric, lactic, tartaric, malic, maleic, isethionic, lactobionic, p-aminobenzoic and succinic acids; organic sulphonic acids such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids such as hydrochloric, sulphuric, phosphoric, sulphamic and pyrophosphoric acids.
For therapeutic use, salts of the compounds of formula (I) will be pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the present invention.
Preferred salts include salts formed from hydrochloric, sulphuric, acetic, succinic, citric and ascorbic acids.
In a further aspect of the invention there are provided the compounds according to the invention for use in medical therapy. The compounds of the present invention are particularly suited to the treatment or prophylaxis of CMV infections and associated conditions. Examples of CMV conditions which may be treated in accordance with the invention have been discussed in the introduction hereinbefore.
According to another aspect, the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. According to a particular embodiment of this aspect of the invention, the viral infection is a herpes virus infection, such as CMV, HSV-1, HSV-2, VZV, EBV, HHV6 or HHV7. A further aspect of the invention includes a method for the treatment or prevention of the symptoms or effects of an HBV infection.
The present invention further provides a method for the treatment of a clinical condition in an animal, for example, a mammal including a human which clinical condition includes those which have been discussed in the introduction hereinbefore, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment or prophylaxis of any of the aforementioned infections or conditions.
In yet a further aspect, the present invention provides the use of a compound according to the invention in the manufacture of a medicament for the treatment or prophylaxis of any of the above mentioned viral infections or conditions.
In addition to the use of compounds of formula (I) in the treatment or prophylaxis of the above viral infections and associated conditions, the compounds may also be used for the treatment or prophylaxis of heart and blood vessel diseases, in particular restenosis and specifically restenosis following angioplasty.
The above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Combination therapies according to the present invention comprise the administration of at least one compound of the formula (I) or a pharmaceutically acceptable derivative thereof and at least one other pharmaceutically active ingredient. The active ingredient(s) and pharmaceutically active agents may be administered simultaneously in either the same or different pharmaceutical formulations or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Preferably the combination therapy involves the administration of one compound according to the invention and one of the agents mentioned herein below.
Examples of such further therapeutic agents include agents that are effective for the treatment of viral infections or associated conditions such as acyclic nucleosides (e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), and acyclic nucleoside phosphonates (e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (HPMC).
The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least one other therapeutic agent, such as those defined hereinbefore.
The compounds according to the invention, also referred to herein as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal and intravitreal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and the chosen active ingredient.
In general a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day. (Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally.) The desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These subdoses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 100 to 400 mg of active ingredient per unit dosage form.
Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound from about 0.025 to about 100 xcexcM, preferably about 0.1 to 70 xcexcM, most preferably about 0.25 to 50 xcexcM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.1 to about 250 mg/kg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
While it is possible for the active ingredient to be administered alone it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Formulations include those suitable for oral, rectal, nasal, topical (including transdermal buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and intravitreal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
The present invention further includes a pharmaceutical formulation as hereinbefore defined wherein a compound of formula (I) or a pharmaceutically acceptable derivative thereof and at least one further therapeutic agent are presented separately from one another and as a kit of parts.
Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1% to 25%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3 (6), 318 (1986).
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerine, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multidose sealed containers, for example, ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavouring agents.
According to a further aspect of the invention, there is provided a process for the preparation of compounds of formula (I) above and derivatives thereof which comprises:
(A) Reacting a Compound of Formula (II) 
(wherein L is hydrogen, or leaving atom or group and R2, R3 and R4 are as hereinbefore defined, Z1 and Z2 are the same or different and are groups R5 and R6 as defined in relation to formula (I) or protected hydroxy groups and Z3 is a group R7 as defined in formula (I) or a protected hydroxy or hydroxymethyl group) with a suitable halogenating agent such as N-bromosuccinamide or when L is a suitable leaving atom or group, for example, a halo atom such as bromine or an organo (for example alkyl) sulphone, or organo (for example alkyl or aralkyl) sulphate such as methylsulphone (MeS(O)2), methylsulphonate (MeS(O)2O) or tosylate (4-MePhS(O)2O) group and R2, R3 and R4, Z1, Z2 and Z3 are as hereinbefore defined, with an amine of formula Hxe2x80x94NR8R9 (wherein R8 and R9 are as hereinbefore defined), a hydrazine of formula Hxe2x80x94NHNR11R12 (wherein R11 and R12 are as hereinbefore defined), an alkylazo of formula Hxe2x80x94NNC1-6 alkyl, an alkoxyamino of formula Hxe2x80x94Nxe2x95x90HOC1-6 alkyl,
or a suitable displacing agent, such as tetrabutyl ammonium azide or sodium or potassium azide;
(B) Reacting a Compound of Formula (III) 
(wherein R1, R2, R3 and R4 are as hereinbefore defined) with a compound of formula (IV) 
(wherein Z1 Z2 and Z3 as hereinbefore defined and L1 is a suitable leaving group or atom in the alpha or beta position, for example, a halo (for example fluoro, chloro or bromo), an alkyl- or aryl-thio (for example phenylthio), or an aryl or aliphatic ester group such as benzoate or acetate;
and thereafter or simultaneously therewith one or more of the following further steps may be additionally performed in any desired or necessary order:
(i) removing any remaining protecting group(s);
(ii) converting a compound of formula (I) or a protected form thereof into a further compound of formula (I) or a protected form thereof;
(iii) converting the compound of formula (I) or a protected form thereof into a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;
(iv) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into the compound of formula (I) or a protected form thereof;
(v) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into another pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;
(vi) where necessary, separating the alpha and beta anomers of the compound of formula (I) or of a protected derivative thereof or of a pharmaceutically acceptable derivative of a compound of formula (I)
Process A may conveniently be used for the preparation of a compound of formula (I) wherein R1 is halogen. Such compounds may conveniently be prepared by reacting a compound of formula (II) wherein L is hydrogen and R2, R3, R4, Z1, Z2 Z3 are as hereinbefore defined with a halogenating agent. Halogenation may be effected in a conventional manner, for example, bromination using a brominating agent such as N-bromosuccinimide (NBS) in an aprotic solvent such as tetrahydrofuran (THF) or preferably 1,4 dioxane heated to 60-150xc2x0 C., preferably 100xc2x0 C.
Compounds of formula (I) wherein R1 is xe2x80x94NR8R9 or xe2x80x94NHNR11R12 (wherein R8, R9, R10 and R11 are as hereinbefore defined), xe2x80x94Nxe2x95x90NC1-6 alkyl, or xe2x80x94NHOC1-6 alkyl may conveniently be prepared from compounds of formula (II) wherein L is a halo atom, such as a bromo or chloro atom, by reaction with an appropriate amine HNR8R9, a hydrazine HNHNR11R12 (wherein R8, R9, R10 and R11 are as hereinbefore defined), an azoalkyl HNxe2x95x90NC1-6 alkyl or alkoxyamine HNHOC1-6 alkyl. Typically, the reaction is effected at an elevated temperature, for example, 70-80xc2x0 C. in an organic solvent such as ethanol or dimethylsulfoxide.
Compounds of formula (I) wherein R1 is azido may advantageously be prepared from compounds formula (II), wherein L is a halo atom, such as bromo or chloro, by reaction with a suitable displacing agent such as sodium or potassium azide or tetrabutyl ammonium azide in an aprotic solvent such as THF or 1,4 dioxane, at an elevated temperature such as 60-150xc2x0 C., more particularly 100xc2x0 C.
Compounds of formula (II) wherein Z1 and/or Z2 are hydroxy groups and/or Z3 is a hydroxy or hydroxymethyl group can, for example, be prepared from a corresponding compound of formula (II) wherein Z1 and/or Z2 are each a protected hydroxy group and/or Z3 is a protected hydroxy or hydroxymethyl group. Conventional protecting groups may be used for Z1, Z2 and Z3. Advantageously ester groups such as those described above in relation, to the esters of the compounds of formula (I) may be used. These protecting groups may be removed either by conventional chemical techniques such as sodium carbonate in methanol or enzymatically, for example, using pig liver enzyme. Alternatively, Z1, Z2 and Z3 may include silyl protecting groups such as tert-butyldiphenyl-, tert-butyldimethyl-, triisopropropyl-silyl groups which may be removed using an appropriate fluoride source, for example HF/Pyridine, n-Bu4NF or Et4NF or a cyclic acetal or ketal such as benzylidene or isopropylidene groups which can be removed under acidic conditions, for example, using tosic acid and methanol.
Alternatively, the compound of formula (II) where Z1 and/or Z2 are protected hydroxy groups and/or Z3 is a protected hydroxy or hydroxymethyl group may be reacted with an agent or under conditions whereby the leaving group L is converted to the desired R1 group simultaneously with removal of the protecting groups. Examples of such agents include cyclopropylamine and other primary and secondary amines providing that these agents are sufficiently nucleophilic and are not sterically hindered.
Compounds of formula (II) wherein L, R2, R3 and R4 are as hereinbefore defined, Z1 is a protected hydroxy group, Z2 is hydrogen and Z3 is a protected hydroxymethyl group may be synthesised from a corresponding compound of formula (II) wherein L, R2, R3 and R4 are as hereinbefore defined, Z1 is a hydroxy group, Z2 is an erythro hydroxy group and Z3 is a hydroxymethyl group according to the procedure of Kawana et al. J. Chem. Soc., Perlan Trans. I, 1989, 1593-1596.
Compounds of formula (II) wherein L, R2, R3 and R4 are as hereinbefore defined, Z1 is hydrogen, Z2 is a protected erythro hydroxy group and Z3 is a protected hydroxymethyl group may be prepared from the corresponding compound wherein C2 is hydroxy using the Bartons deoxygenation process as described in D. H. R. Barton, J.Cs. Jaszberenyl Tetrahedron Lett. 1989, 30, 2619-2622. The C2 hydroxy compound referred to above may be prepared from the corresponding ribose compound by treatment with an appropriate protecting agent or agents, for example, a silylating agent such as 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in the presence of a solvent such as pyridine and at a temperature range of 5-70xc2x0 C. and preferrably at ambient temperature.
Compounds of formula (I) wherein R1 is as hereinbefore defined and compounds of formula (II) wherein L is as hereinbefore defined may be prepared by reacting a compound of formula (V) 
(wherein R2, R3 and R4 are as hereinbefore defined and X is equivalent to R1 or L as hereinbefore defined), with a compound of formula (IV) 
(wherein Z1, Z2, Z3 and L1 are as hereinbefore defined).
The reaction of the compounds of formula (IV) and (V) may be effected using a Lewis acid such as trimethylsilyl triflate, stannic tetrachloride, or boron trifluoride, the former being preferred. The reaction is generally effected in an aprotic solvent and at an elevated temperature, for example, in acetonitrile at 15-30xc2x0 C. or 1,2-dichloroethane at 70-90xc2x0 C.
The compound of formula (V) is advantageously trimethylsilylated at the N1-position in the above procedures to improve solubility; for example by treatment with trimethylsilyl chloride, hexamethyl disilazane or, most preferably, N,O-bis-trimethylsilyl acetamide (BSA). This silylation can be effected in a solvent preferably 1,2-dichloroethane or acetonitrile preferably at 70-80xc2x0 C. After completion of the silylation reaction, a Lewis acid may be added followed by addition of the compound of formula (IV).
Compounds of formula (IV) may be produced by conventional methods prior to coupling with the base or derived by modification of another sugar moiety which is already part of a nucleoside. For example, compounds of formula (IV) wherein L1 is as hereinbefore defined, Z1 is hydroxy or a protected hydroxy group, Z2 is an erythro hydroxy or a protected erythro hydroxy group and Z3 is hydroxymethyl or a protected hydroxymethyl group, may be prepared by methods analogous to those known for D-ribose derivatives or by methods readily available from the chemical literature, for example, by methods described in Acton et al. J. Am. Chem. Soc, 1964, 86, 5352. A preferred compound of formula (IV) is the compound wherein Z1 Z2 and L1 are each OC(O)CH3 and Z3 is xe2x80x94CH2OC(O)CH3. This compound may be prepared in an analogous manner to that developed for D-ribose (R. D. Guthrie and S. C. Smith., Chemistry and Industry, 1968, pp 547-548), followed advantageously by recrystallisation from ethanol.
Compounds of formula (IV) wherein L1 is as hereinbefore defined, Z1 and Z2 are protected erythro hydroxy groups and Z3 is CH3 or CH2R13 wherein R13 is a halo atom including Cl, Br, F and I, may be synthesised from the corresponding sugar moiety wherein C1 is an appropriate ether group such as an aryloxy, arylalkyloxy (e.g. benzyloxy) or alkoxy (e.g. methoxy) by treatment with an appropriate esterifying agent, such as an acylating agent, for example, an acid anhydride, such as acetic anhyridie or benzoic anhydride in the presence of a mineral acid, for example, sulphuric acid. The reaction may be done at a temperature of xe2x88x9220 to 30xc2x0 C. and preferrably at a temperature of 5xc2x0 C. in a solvent such as acetic acid.
Such ethylated compounds may be synthesised from the corresponding C2, C3 diol by treatment with an appropriate esterifying agent such as an acylating agent, for example, an acid anhydride such as acetic or benzoic anhydride in an appropriate solvent such as pyridine or in an organic solvent such as acetonitrile in the presence of a base, for example, triethylamine (TEA) and a nucleophilic catalyst such as N1N-dimethylaminopyridine (DMAP). Such diol compounds may conveniently be prepared by cleavage of the corresponding C2, C3 cyclic ether compound by treatment with a weak acid such as Dowex 50 in the presence of an alcohol, for example, methanol. Appropriate cyclic ethers include cyclic ketals, for example, isopropylidine.
Cyclic ether compounds wherein Z3 is CH3 may be prepared by dehalogenation of the corresponding compound wherein Z3 is a CH2halo group, for example, CH2Cl or CH2F. Typically the reaction is carried out in the presence of a free radical initiater, such as -azo-iso-butyronitrile (AIBN), a solvent, for example, toluene and at a temperature in the range of 70 to 110xc2x0 C. for example 90xc2x0 C. Compounds wherein Z3 is a CH2halo group may be prepared by halogenation of the corresponding sugar moiety wherein Z3 is CH2OH. Halogenation may be effected in a conventional manner, for example, chlorination using an agent such as triphenyl phosphine (Ph3P) in an organic solvent, for example, acetonitrile.
Such halomethyl compounds may be prepared from commercially available L-ribose by treatment with an alcohol, for example, methanol in a mineral acid, for example, sulphuric acid in a temperature range of 0-50xc2x0 C., conveniently at room temperature, followed by treatment with an protecting agent, such as 2,2-dimethoxypropane in an appropriate aprotic solvent such as tetrahydrofuran or preferrably 2,2-dimethoxypropane itself. The reaction may be carried out in a temperature range of minus 10 to 60xc2x0 C. and preferrably at ambient temperature.
Compounds of formula (IV) wherein L1 is as hereinbefore defined, Z1 is an erythro protected hydroxy group, Z2 is a threo protected hydroxy group and Z3 is a protected hydroxymethyl group may be synthesised from L-xylose in a manner analogous to that described by Gosselin et al (Nucleic Acid Chemistry Improved and New Synthetic Procedures, Methods and Techniques, Part 4. Ed. L B Townsend, R S Tipson) starting from D-xylose.
Compounds of formula (IV) wherein L1 is as hereinbefore defined, Z1 and Z2 are protected erythro hydroxy groups and Z3 is hydrogen may conveniently be prepared by treating the corresponding sugar moiety wherein C1 is hydroxy and C2 and C3 are ether groups, for example, cyclic ketals such as isopropylidine. Such vicinal sugar moieties may be prepared by the method described by Hudlicky et al 1990, J. Org. Chem., 55, 4683.
Compounds of formula (V) wherein X is L or a xe2x80x94NR8R9 group (wherein L, R8 and R9 are as hereinbefore defined), may be prepared in accordance with the methods described in PCT specification WO92/07867 incorporated herein by reference.
Alternatively, compounds of formula (V) wherein X is R and R is a group xe2x80x94NR8R9 wherein R8 and R9 are as hereinbefore defined may be prepared by reacting a compound of formula (VI). 
with an agent or agents capable of cyclising the diamine into a benzimidazole. Typically compounds of formula (I) may be reacted with an isothiocyanate of formula (VII)
Sxe2x95x90Cxe2x95x90NR8R9xe2x80x83xe2x80x83(VII)
wherein R8 and R9 are as hereinbefore defined.
The reaction may be carried out in the presence of a carbodiimide such as dicyclohexyl carbodiimide or 1-cylohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluene-sulphonate conveniently in the presence of an aprotic aromatic solvent such as toluene and most preferably pyridine and at an elevated temperature, preferably 75-150xc2x0 C.
Compounds of formula (V) wherein X is hydrogen may be obtained commercially or alternatively may be prepared by reacting a compound of formula (VI) with formamidine under aqueous acidic conditions, at room temperature to 80xc2x0 C.
Compounds of formula (VI) may be prepared from the appropriate corresponding othro nitro aniline in the presence of a reducing agent such as reduced iron, for example, in the presence of an acid, most preferably hydrochloric acid. This reaction is typically carried out in the presence of a solvent, ethyl alcohol for example, in a temperature range of 50-78xc2x0 C. (B. Fox and T. L. Threfall, Org. Syn. Coll. Vol. 5, 1973, p. 346). Alternatively, such ortho phenylenediamines may be prepared in the presence of a reducing agent such as catalytic Raney nickel, also in the presence of hydrogen. This reaction is typically run in the presence of a solvent, ethyl alcohol for example, at ambient temperatures (K. Dimroth, et al, Org. Syn. Coll. Vol. 5, 1973, p. 1130). More particularly, such ortho phenylenediamines may be prepared by methods described in the literature.
Compounds of formula (VI) and (VII) may be prepared by methods well known to a skilled person or readily available in the chemical literature or obtained commercially.
Esters according to the invention may be prepared by methods well known in the art, for example, a compound of formula (I) may be converted into a pharmaceutically acceptable ester by reaction with an appropriate esterifying agent, for example, an appropriate acid halide or anhydride.
A compound of formula (I) may be converted into a corresponding pharmaceutically acceptable ether of formula (I) by reaction with an appropriate alkylating agent in a conventional manner.
The compounds of formula (I) including esters thereof, may be converted into pharmaceutically acceptable salts thereof in conventional manner, for example by treatment with the appropriate acid. An ester or salt of an ester of formula (I) may be converted into the parent compound, for example, by hydrolysis.
The beta and alpha anomers may be separated and isolated in pure form by silica gel chromatography using a single solvent or a combination of solvents such as 1:20 methanol:dichloromethane.